High density lipoprotein metabolism

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Meagan Matthews
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1 High density lipoprotein metabolism

2 Lipoprotein classes and atherosclerosis Chylomicrons, VLDL, and their catabolic remnants Pro-atherogenic LDL HDL Anti-atherogenic

3 Plasma lipid transport Liver VLDL FC FC TG FFA TG LPL LDL FFA Adipose and other tissues Adipose tissue TP TG Liver LDL receptor LDL receptor Bile HDL TG LCAT ABCA1 FC New synthesis Cell in peripheral tissue

4 HDL and cardiovascular disease

Hazard Ratio Coronary heart disease and HDL-C 3.5 3.0 2.5 2.

5 Hazard Ratio Coronary heart disease and HDL-C N = 302,430 Adjusted for age and gender Adjusted for multiple factors HDL-C (mmol/l) The Emerging Risk Factors Collaboration. JAMA 2009;302:

6 What are HDLs?

7 Structure of HDL Surface monolayer of phospholipids and free cholesterol apoa-i apoa-ii Hydrophobic core of triglyceride and cholesteryl esters

8 HDL are heterogeneous COMPOSITION APOLIPOPROTEINS ApoA-I, apoa-ii, apoa-iv, apoe, others LIPIDS TG,, FC, PL SIZE: nm SHAPE: spherical, discoidal CHARGE: prebeta, alpha

9 HDL Charge and shape Lipid-poor apoa-i Prebeta mobility Discoidal Prebeta mobility Spherical Alpha mobility

10 HDL Subpopulations PARTICLE SHAPE APOLIPOPROTEIN COMPOSITION Discoidal Spherical A-I HDL A-I/A-II HDL PARTICLE SIZE Lipid-poor apoa-i HDL 2b HDL 2a HDL 3a HDL 3b HDL 3c

11 This HDL heterogeneity is the result of activity of several factors that assemble and remodel HDL in plasma

12 Origin of apoa-i LIVER INTESTINE Chylomicrons Lipid-poor apoa-i Lipolysis

13 Factors that assemble and remodel HDL in plasma ABCA1 LCAT TP Hepatic lipase PLTP SRB1

14 Factors that assemble and remodel HDL in plasma ABCA1 LCAT TP Hepatic lipase PLTP SRB1

15 Lipidation of apoa-i Lipid-poor apoa-i Cell membrane ABCA-1 phospholipid, cholesterol Discoidal HDL

16 Factors that assemble and remodel HDL in plasma ABCA1 LCAT TP Hepatic lipase PLTP SRB1

17 LCAT (lecithin:cholesterol acyltransferase) LCAT catalyses the reaction: phosphatidylcholine lysophosphatidylcholine unesterified cholesterol cholesteryl ester

18 LCAT The LCAT reaction is responsible for most of the cholesteryl esters circulating in plasma HDLs are the preferred substrates for LCAT LCAT is activated by apoa-i, apoa-iv, apoe LCAT NOT activated by apoa-ii

19 Role of LCAT in formation of spherical HDL Liver Intestine Free cholesterol transferred from cell membranes (including liver and intestine) apoa-i free cholesterol LCAT cholesteryl esters Discoidal HDL Spherical HDL

20 Factors that assemble and remodel HDL in plasma ABCA1 LCAT TP Hepatic lipase PLTP SRB1

21 Role of TP in plasma cholesterol transport Liver LDL-R SR-B1 FC SR-B1 TP VLDL/LDL Bile HDL LCAT FC Extrahepatic Tissues (including the artery wall Free Cholesterol

22 Shuttle mechanism HDL TP TP TRL TG TG TG TG TG TP TG TP TG LDL Barter et al; Biochem J. 1982; 208:1. Swenson et al. J. Biol. Chem. 1988; 263:5150. Tall. J. Lipid Res.1993; 34:1255.

23 TP plays a major role in remodelling of HDL, especially when acting in the presence of hepatic lipase

24 Factors that assemble and remodel HDL in plasma ABCA1 LCAT TP Hepatic lipase PLTP SRB1

25 HEPATIC LIPASE Hepatic lipase catalyses the hydrolysis of triglyceride and phospholipids in HDL Remodelling of HDL by hepatic lipase is most dramatic when linked to activity of TP

26 Role of TP and hepatic lipase in the remodelling of HDL HDL TGR-LP TG TP TG HDL TG Lipid-free/poor apoa-i TG HL FFA TG Excretion through kidney Small, dense HDL Rye et al Atherosclerosis, 1999,145:227 Rye et al Arterioscler Thromb Vasc Biol, 2004, 24: 421.

27 Factors that assemble and remodel HDL in plasma ABCA1 LCAT TP Hepatic lipase PLTP SRB1

28 PLTP (phospholipid transfer protein) PLTP catalyses the transfer of phospholipids between plasma lipoproteins PLTP also remodels HDL

29 Remodelling of AI-HDL by PLTP PLTP PLTP PLTP lipid-poor apoa-i

30 Factors that assemble and remodel HDL in plasma ABCA1 LCAT TP Hepatic lipase PLTP SRB1

31 SRB1 (scavenger receptor type B1) SRB1 promotes the selective hepatic uptake of HDL cholesteryl esters SRB1 thus also remodels HDL

32 Remodelling of AI-HDL by SRB1 Liver Lipid-poor apoa-i SRB1 TG Larger HDL TG Smaller HDL

33 Apolipoprotein-specific HDL apoa-i apoa-i TG TG apoa-ii Spherical AI-HDL Spherical AI/AII-HDL

34 Origin of AII-HDL Secretion LIVER Lipid-poor apoa-ii phospholipids from cell membranes Discoidal AII-HDL

35 LCAT-mediated formation of spherical AI/AII-HDL Discoidal AI-HDL LCAT Spherical AI-HDL LCAT Fusion Spherical AI/AII-HDL TG LIVER Discoidal AII-HDL

36 Remodelling of HDL generates lipid-poor apoa-i

37 Remodelling of HDL generates lipid-poor apoa-i TG TP HL PLTP SRB1 TG Lipid-poor apoa-i

38 Fate of lipid-poor apoa-i Lipid-poor apoa-i Acquire PL from cells (via ABCA1) to form discoidal HDL Discoidal AI-HDL Incorporation into spherical AI-HDL Excretion through kidney Small, spherical AI-HDL LCAT Large, spherical AI-HDL

39 Cycling of apoa-i between HDL and a HDL TP HL PLTP SRB1 TG lipid-poor pool Lipid-poor apoa-i Excretion through kidney Discoidal HDL TG UC LCAT TG

40 Functions of HDL

41 Role of HDL in promoting efflux of cholesterol from cells

42 Efflux of cholesterol from cells Extracellular space Cell membrane Lipid-poor apoa-i ABCA1 FC,PL

43 Efflux of cholesterol from cells Extracellular space Cell membrane Lipid-poor apoa-i ABCA1 FC,PL Discoidal HDL

44 Efflux of cholesterol from cells Extracellular space Cell membrane Lipid-poor apoa-i Discoidal HDL ABCA1 ABCA1 SR-B1 FC,PL FC

45 Efflux of cholesterol from cells Extracellular space Cell membrane Lipid-poor apoa-i Discoidal HDL LCAT ABCA1 ABCA1 SR-B1 FC,PL FC Small spherical HDL

46 Efflux of cholesterol from cells Extracellular space Cell membrane Lipid-poor apoa-i Discoidal HDL LCAT ABCA1 ABCA1 SR-B1 FC,PL FC Small spherical HDL Diffusion SR-B1 ABCG1 FC

47 Efflux of cholesterol from cells Extracellular space Cell membrane Lipid-poor apoa-i Discoidal HDL LCAT Small spherical HDL LCAT ABCA1 ABCA1 SR-B1 Diffusion SR-B1 ABCG1 FC,PL FC FC Larger spherical HDL

48 Efflux of cholesterol from cells Extracellular space Cell membrane Lipid-poor apoa-i Discoidal HDL LCAT Small spherical HDL LCAT ABCA1 ABCA1 SR-B1 Diffusion SR-B1 ABCG1 FC,PL FC FC Larger spherical HDL Diffusion SR-B1 ABCG1 FC

49 Protective properties of HDLs Promote cholesterol efflux from macrophages Anti-oxidant properties Anti-thrombotic properties Anti-inflammatory properties Improve endothelial function Promote endothelial repair Improve glycemic control Other

50 Conclusions The concentration of HDL-C correlates inversely with CV risk

51 Conclusions The concentration of HDL-C correlates inversely with CV risk HDL particles have many properties with the potential to protect

52 Conclusions The concentration of HDL-C correlates inversely with CV risk HDL particles have many properties with the potential to protect HDL particles are assembled in the plasma compartment

53 Conclusions The concentration of HDL-C correlates inversely with CV risk HDL particles have many properties with the potential to protect HDL particles are assembled in the plasma compartment The HDL fraction in human plasma is heterogeneous in terms of particle size, charge and composition

54 Conclusions The concentration of HDL-C correlates inversely with CV risk HDL particles have many properties with the potential to protect HDL particles are assembled in the plasma compartment The HDL fraction in human plasma is heterogeneous in terms of particle size, charge and composition HDL particles are extensively remodelled in plasma by a variety of proteins and enzymes

55 Conclusions The concentration of HDL-C correlates inversely with CV risk HDL particles have many properties with the potential to protect HDL particles are assembled in the plasma compartment The HDL fraction in human plasma is heterogeneous in terms of particle size, charge and composition HDL particles are extensively remodelled in plasma by a variety of proteins and enzymes Deficiencies of these remodelling factors result in major changes to HDL particles

56 Unanswered questions Q. Which HDL subpopulations (if any) protect against CV disease? Answer: We do not know Q. Which (if any) of the known HDL functions protect against CV disease? Answer: We do not know Answers to these questions require much more research

Lipid/Lipoprotein Structure and Metabolism (Overview)

Lipid/Lipoprotein Structure and Metabolism (Overview) Philip Barter President, International Atherosclerosis Society Centre for Vascular Research University of New South Wales Sydney, Australia Disclosures